4-(thienyl-2&#39;&#39;)-and 4-(pyridyl-3&#39;&#39;)-5-aminopyrazoles



United States Patent 3,041,343 4-('IH[ENYL-2")- AND 4-(PYRlDYL-3")-5-AMINOPYRAZOLES Ernst Jncker, Binningen, Basel-Land, and Adolf J.Lindemnann, Basel, Switzerland, assignors to Sandoz Ltd., Basel,Switzerland No Drawing. Filed Sept. 20, 1960, Ser. No. 57,120 Claimspriority, application Switzerland Oct. 14, 1959 9 Claims. (Cl. 260-293)The present invention relates to a novel and useful more especiallytherapeutically useful-group of S-aminopyrazoles of the formula whereinR and R each stands for an alkyl group straight-chained orbranch-chained-with l to 4 carbon atoms (e.g. methyl, propyl, isopropyl,isobutyl, etc.) and R stands for the Z-thienyl radical or for the3-pyridyl radical l Bi wherein R has the precedingly-recitedsignificance.

The preparation of the new S-aminopyrazoles 1, substituted in the1-position by an N-alkyl-4-piperidyl radical and in the 4-position bythe 2-thienyl or the 3-pyridyl radical, may for example conveniently becarried out as follows: A suspension of an acylacetic acid nitrile ofFormula IIe.g. a-propionyl-thienyl-(2) -acetonitri1ein an anhydrousorganic solvent, such for example as glacial acetic acid, has stirredthereinto at room temperature (about to about C.), a solution of ahydrazine derivative of formula I[Ie.g. N-methyl-piperidyl-4hydrazineinthe same solvent. To assure completion of the ensuing reaction, stirringis then continued for two more hours at room temperature. After removalof the solvent in vacuo from the obtained reaction mixture, the desiredreaction product is isolated, e.g. by distillation in a high vacuum, andif desired may then be purified by crystallization.

The new compounds I of the present invention are crystalline or liquidat room temperature and can be dis- 3,041,343 Patented June 26, 1962tilled in a high vacuum without undergoing decomposition. They are basiccompounds which form stable therapeutically useful water-soluble salts,crystalline at room temperature, with a wide variety of inorganic andorganic acids. Thus, for example, with hydrochloric, tartaric, acetic,phosphoric, maleic, citric, benzenesulfonic acids, etc., they form thecorresponding hydrochlorides, tartrates, acetates, phosphates, maleates,citrates, benzenesulfonates, etc.

The new pyrazoles I as well as their salts with acids possessoutstanding pharmacodynamic properties which render them excellentlysuitable for use in therapy. Thus, while being of low toxicity, theyexert antiphlogistic, analgetic, antiypyretic and adrenolytic actionsand possess, more especially, a specific antirheumatic activity. Inaddition, they comprise compounds with a serotonin-inhibiting action.

For example, testing, the antiphlogistic (inflammation inhibiting)action on formalin oedema in the rat paw upon subcutaneousadministration of:

(a) 1-(N-methyl-piperidyl-4)-3-methyl-4(thienyl 2")- S-aminopyr-azole;

(b) 1-(N-methyl-piperidyl-4')3-ethyl-4-(thienyl-2) 5- aminopyrazole; and

(c) 1-(N-iscpropyl-piperidylt')-3-ethyl-4-(thienyl 2")- S-aminopyrazole,

gives the following average inhibition of the formalin oedema:

TABLE 1 Average Inhibition of Formalin Oedema in percent afterAdministration oi Substance 5 mgJkg. 10 mgJkg. 20 mgJkg. 50 mgJkg Thefollowing table (Table H) shows the inhibition of serotonin oedema inthe rat paw after subcutaneous administration of the compounds a, b and0:

The negative percentages in Tables I and II indicate the lessermagnitudes in which the oedema appears in the pro-treated subjects thanin untreated control subjects.

The antipyretic action in feverish rats is exemplified by the fact that1-(N-methyl-piperidyl-4')3-n-butyl-4- (thienyl-2")-5-aminopyrazole,intravenously administered in a dose of about '10 mg./kg., brings abouta temperature drop of at least 0.7 C.

Since, as aforestated, the new pyrazoles I are readily convertible intowater-soluble salts thereof with inorganic and organic acids, thepresent invention renders available for therapeutic purposes pyrazolederivatives which are distinguished by particularly good resorbability,so that they may be administered per os, e.g. in tablet form. There isalso made readily possible the preparation of highly concentratedsolutions which in many cases are indispensable for parenteral stosstherapy. In addition, the

ofi at about 40 under reduced pressure.

new compounds are useful as intermediates for the preparation of othertherapeutically useful products.

The acylacetic acid nitriles of formula 11 may be prepared by knownmethods, for example by reacting thienyl- (Z-acetonitrile orpyridyl-(3)-acetonitrile with the appropriate acetic acid-, propionicacidor valerianic acid-esters.

The compounds of Formula 111, wherein R is a lower alkyl group, can beprepared by condensing an N-alkyl- 4piperidone with amonoacyl-hydrazine, catalytically reducing the resulting acyl-hydrazoneto the acylated hydrazine derivative, and then splitting 01f the acylgroup by heating with aqueous mineral acid.

In the following examples which, by way of illustration only, set forthpresently preferred embodiments of the invention, the parts are byweight unless otherwise indicated. Parts by weight bear the samerelationship to parts by volume as do grams to milliliters. Temperaturesare in degrees centigrade; melting points and boiling points areuncorrected.

Example 1 A solution of 16.0 parts of a-acetyl-thienyl-(2)-acetonitrileand 12.5 parts of N-methyl-piperidyl-4-hydrazine in 225 parts by volumeof absolute ethanol is allowed to stand for one hour at roomtempera-tore and is then heated to boiling under reflux for 3 hours. Theethanol is then evaporated oif under reduced pressure and thedark-brown, thickly viscous residue is distilled in a high vacuum (0.1mm. Hg), whereupon the desired l-(N methyl-piperidyl 4')-3-methyl4-(thienyl-2")-5- aminopyrazole goes over at between 179 and 210 underthe said pressure of 0.1 mm. Hg and solidifies in the condenser. Afterrecrystallization from benzene, the new compound melts at 9799.

Example 2 A solution of 10.8 parts of N-methyl-piperidyl-4-hydrazine in37 parts by volume of glacial acetic acid is stirred dropwise into asuspension of 15.0 parts of a-propionylthienyl-(2)-acetonitrile in 37parts by volume of glacial acetic acid, care being taken that thetemperature does not exceed 30. The dark gray-brown reaction mixture isthen further stirred for two more hours at room tempcrature, after whichthe glacial acetic acid is distilled off at 40 under reduced pressure.The residue is taken up in 250 parts by volume of water, and theresultant aqueous solution is adjusted to alkalinity by and saturatedwith sodium carbonate, whereupon a dark-brown resinous mass separatesout. This is extracted with a total of 700 parts by volume ofchloroform, the combined chlorofrom extracts dried over magnesiumsulfate, and the chloroform removed under reduced pressure. Theso-obtained crystalline residuel-(N-methyl-piperidyl-4')-3'ethyl-4(thienyl-2")-5 aminopyrazole-is recrystallized from benzene, whereuponit melts at 129- 130'.

The a-propionyl-thienyl-(Z)-acetonitrile is prepared by reactingthienyl-(2)-acetonitrile in ethanolic solution with ethyl propionate inthe presence of sodium ethylate. M.P. 8991 after crystallization fromether-petroleum ether.

Example 3 A solution of 4.75 parts of N-isopropyl-piperidyl-4-hydrazinein 13 parts by volume of glacial acetic acid is stirred dropwise into asuspension of 5.4 parts of a-propionyl-thienyl-(Z)-acetonitrile in 13parts by volume of glacial acetic acid, care being taken that thetemperature does not exced 50. The dark gray-brown reaction mixture isthen further stirred for two more hours at room temperature, after whichthe glacial acetic acid is distilled The residue is distilled in a highvacuum (0.01 mm. Hg), the desired l-(N isopropyl-piperidyl4)-3-ethyl4-(thienyl-2")-5- aminopyrazole passing over as a thickly viscousbrownish 4 yellow oil at betwen 175 and 205 under the said pressure of0.01 mm. Hg. The distillate is then dissolved in a small quantity ofmethanol and the calculated amount of a methanolic maleic acid solutionadded. The solution is then concentrated under reduced pressure, afterwhich ether is slowly added, whereupon the I-(N-isopropyl-piperidyl-4')-3-ethyl-4 thienyl-2")S-aminopyrazole-bis-maleate separates out in crystalline form. After tworecrystallizations from methanol-ether, the said bis-maleate melts at131-132.

Example 4 A solution of 3.2 parts of N-methyl-pi-peridyl-4-hydrazinc in12 parts by volume of glacial acetic acid is stirred dropwise in thecourse of 20 minutes into a suspension of 5.1 parts ofa-valeroyl-thienyl-(2)-acetonitrile in 12 parts by volume of glacialacetic acid, care being taken that the temperature does not exced 50.The dark brown reaction solution is then further stirred for two morehours at room temperature, after which the glacial acetic acid isdistilled oif at 4050 under reduced pressure. The residue is taken up inparts by volume of water, and while cooling the same with ice, theaqueous solution is adjusted to alkalinity by and saturated withpotassium carbonate, whereupon a dark-brown resinous mass separates out.It is extracted with a total of parts by volume of chloroform, thecombined chloroform extracts dried over magnesium sulfate, and thechloroform removed under reduced pressure. The soobtained residue isdistilled under a pressure of 0.01 mm. Hg, whereupon the desiredl-(N-methyl-piperidyl-4)-3- n-butyl4-(thienyl-2")-5-aminopyrazoledistills over at an air-bath temperatm'e of 180-2l0.

To prepare the bis-maleate, the yellow-brown thickly viscous distillateis taken up in 10 parts by volume of absolute ethanol, after which asolution of 4.3 parts of maleic acid in '10 parts by volume of absoluteethanol is added. The solvent is then removed under reduced pressure andthe crystalline residue-1-(N-methyl-piperidyl-4')-3-n-butyl 4-(thienyl2")-5-aminopyrazole bismaleateis twice recrystallized frommethanol-ether. The so-obtained colorless crystals melt at 128-430.

The u-valeroyl-thienyl(2)-acetonitrile is obtained by reactingthienyl-(Z) -acetonitrile in ethanolic solution with 6.9 parts of thesodium salt of a-(pyridyl-3)acetoacetic acid nitrile in 70 parts byvolume of glacial acetic acid are heated to 40 for 15 minutes. Aftercooling to 20, a solution of 4.9 parts of N-methyl-piperidyllhydrazinein 8 parts by volume of glacial acetic acid is stirred in dropwise, carebeing taken that the temperature does not exceed 40. The reactionmixture is then further stirred for five hours at room temperature,allowed to stand overnight, and the glacial acetic acid distilled off at40-50" under reduced pressure. The residue is taken up in 100 parts byvolume of water, washed with a total of 120 parts by volume of ether,the aqueous solution adjusted to alkalinity by and saturated with sodiumcarbonate and extracted with a total of 180 parts by volume ofchloroform. After drying the chloroform 5 yieldsa(pyridyl-3)-acetoacetic acid nitrile. M.P. 194-- 196".

In like manner, other 4-(pyridyl-3")-5-aminopyrazole derivatives such ase.g. 1-(N-isopropyl-piperidyli)-3- methyl4(pyridyl 3")-5-aminopyrazole,l-(N-methylpiperidyl-4')-3-ethyl-4 (pyridyl-3)-5-aminopyrazo1e or l-(Nmethyl piperidyl-4')-3-n-butyl 4-(pyridyl-3")-5- aminopyrazole canmutatis mutandis be prepared in manner analogous to the above-describedpreparation of 1-(N-methylpiperidyl-4')-3-methy1-4-(pyridyl-3")-5-aminopyrazole, byemploying the corresponding starting compounds II and 111.

Having thus disclosed the invention, what is claimed is:

1. A compound of the formula wherein each of R and R is an alkyl groupwith 1 to 4 carbon atoms, and R is Z-thienyl. 2. A compound of theformula R:IJ -fiB-: mN-o N compound of the formula BIN-i l wherein eachof R and R is an alkyl group with 1 to 4 carbon atoms, and R is3-pyridyl.

5. 1 (N methyl piperidyl 4) 3 methyl 4- (-thienyl-2")-5-aminopyrazo1e.

6. 1 (N methyl piperidyl 4') 3 ethyl 4- (thienyl-2")-5-aminopyrazole.

7. 1 (N isopropyl piperidyl 4') 3 ethyl 4- (thienyl-2")-5-aminopyrazole.

8. 1 (N methyl piperidyl 4') 3 n butyl 4- 35(thienyl-2")-5-aminopyrazole.

9. 1 (N methyl piperidyl 4') 3 methyl 4- (pymidyl-3")-5-aminopyrazole.

References Cited in the file of this patent Richters Organic Chemistry(Textbook), 3rd edition, vol. 4, pages 22-25, 195 and 196 (1947).Elsevier Publishing Co., I'nc., New York, N.Y.

1. A COMPOUND OF THE FORMULA
 2. A COMPOUND OF THE FORMULA